Damage of an arterial vessel wall leads to platelet adhesion, aggregation and ultimately may result in thrombosis. These events are known to contribute to the development of occlusive syndromes in the coronary, cerebral and peripheral vascular system, as well as restenosis and intimal hyperplasia that occur after angioplasty, atherectomy and arterial stenting (1;2). In both thrombosis and reocclusion, platelets adhere to the subendothelium of damaged blood vessels through an interaction with von Willebrand factor (vWF) that forms a bridge between collagen, a component of the damaged vessel wall and the platelet glycoprotein Ib (GPIb) (3). This reversible adhesion or tethering of the platelets at high shear rate is followed by a firm adhesion through the collagen receptors (GPIa-IIa; GWPIV, . . . )(4) resulting in platelet activation and release of ADP, thromboxane, and serotonin. These in turn activate additional platelets and trigger the conformational activation of the platelet GPIIb/IIIa receptor, leading to fibrinogen binding and finally to platelet aggregation (5). Ultimately, a platelet-initiated thrombus is formed.
The search for anti-platelet drugs in the prevention of thrombosis has recently focused on the blockade of the GPIIb-IIIa receptor and on the inhibition of the vWF-GPIb axis. The best characterized drugs are antibodies and peptides that block the binding of adhesive proteins to GPIIb-IIIa which have been tested in animal models and of which many are being tested in clinical trials and/or are used in the clinic (6-8). Also compounds that interfere with the vWF-GPIb axis inhibit thrombus formation in various animal models. The GPIb/IX/V complex consists of 4 different polypeptides GPIbα, GPIbβ, GPIX and GPV which are all members of the leucine-rich protein family (9; 10). The N-terminal domain of the GPIbα polypeptide contains the vWF binding site (11). vWF is composed of several homologous domains each covering different functions: it interacts through its A1 domain mainly with the GPIb/V/IX complex (12), whereas its A3 domain predominantly interacts with fibrillar collagen fibers (13; 14). Compounds that interact with GPIbα, like the GPIb-binding snake venom proteins echicetin and crotalin (15; 16), an anti-guinea pig GPIb antibody (17; 18), a recombinant A1 domain fragment (VCL) (2;23) and recently an anti-human GPIb antibody (19) or compounds that bind to vWF like anti-A1-vWF-monoclonal antibodies (mAbs) (20; 21), aurin tricarboxylic acid (ATA) (22) are inhibiting in vivo thrombus formation.
Specific blockade of the vWF-collagen interaction in vivo has not yet been demonstrated but could be a novel strategy for the prevention of thrombus formation in stenosed arteries. We here describe for the first time the antithrombotic effect of a murine anti-human vWF mAb82D6A3, known to bind to the A3-domain and to inhibit vWF binding to fibrillar collagens type I, III and calf's skin collagen but not to collagen VI (24), Vanhoorelbeke et al., 2000b).
The present study aimed to evaluate the antithrombotic efficacy of mAb 82D6A3 in baboons by using a modified Folts' model, where cyclic flow reductions (CFRs) due to thrombus formation and its dislodgment are measured in an artery following intimal damage and placement of a critical stenosis to reduce the lumen diameter (25).